FDA's Unimproved Enforcement of Postmarketing Requirements and Commitments: Implications for Providers and Patients

Highlights

• The Food and Drug Administration (FDA) is empowered to require and enforce postmarketing studies for prescription drugs.

• Overall trends indicated no change in FDA oversight of PMRs/PMCs between 2009-2010 and 2011–2014.

• The findingss are consistent with previous literature and suggest no improvement in the FDA's oversight since 2010.

Abstract

Background

The 2007 reauthorization of the Prescription Drug User Fee Act empowered the Food and Drug Administration (FDA) to require and enforce postmarketing studies to monitor the safety of prescription drugs, an increasing number of which are approved under expedited development or review programs. However, compliance rates for postmarketing requirements are low, and the FDA has not exercised its enforcement authority, allowing the very safety concerns that prompted the expansion of its power to continue. Prior evaluations have found that the FDA lacks reliable, timely, and readily accessible data for tracking postmarket safety issues, and that it has failed to enforce the postmarket surveillance measures it requires of the pharmaceutical industry.

Objective

This study provides an updated evaluation of FDA oversight of postmarketing requirements and commitments and assesses whether there have been improvements since 2010.

Methods

This study utilized data from the FDA's annual Report on the Performance of Drug and Biologics Firms in Conducting Postmarketing Requirements and Commitments. It evaluated studies opened in FY 2011–2014 and tracked their status through the FDA's FY 2018 report (data as of September 30, 2018), thereby allowing the pharmaceutical industry 4–7 years to complete a given PMR/PMC.

Descriptive statistics were calculated, and differences in the status of postmarketing requirements and postmarketing commitments between FYs 2011–2014 and FY 2009–2010 were evaluated.

Results

During fiscal years 2011–2014, there was little difference in the FDA's oversight of postmarketing studies compared to fiscal years 2009–2010. While there were some year-to-year significant differences, the overall trend indicated no change.

Conclusions

The FDA's oversight of postmarketing studies has not improved since 2010. This paper discusses implications for providers and patients who unduly assume the responsibility of postmarketing surveillance due to the lack of FDA oversight.

Introduction

The 1992 Prescription Drug User Fee Act (PDUFA) established pharmaceutical industry user fees, created a framework for reauthorization consultation with the pharmaceutical industry, and required the Food and Drug Administration (FDA) to review standard applications within 12 months and applications for drugs determined by the FDA to treat serious or life-threatening conditions within 6 months. PDUFA II (1997) phased in a reduction in review times for standard applications from 12 months to 10 months.^1,2 PDUFA IV (2007) authorized additional fee revenues of $225 million over a 5-year period to support drug safety activities¹ and the FDA to require and enforce postmarketing studies for prescription drugs.3, 4, 5

Required studies or trials are called postmarketing requirements (PMRs), whereas studies that applicants agree to conduct voluntarily are called postmarketing commitments (PMCs). The FDA can require a study or trial to assess a known serious risk related to a drug, to assess signals of serious risk related a drug, or to identify unexpected serious risks when available data raises concerns. All postmarketing studies have a required timetable, including dates for trial completion and submission of final protocols and reports.3, 4, 5 Applicants must submit annual status reports (ASRs) for PMRs/PMCs within 60 days of the anniversary of the medication's approval.⁶ Failure to meet these requirements is considered a violation, absent good cause for noncompliance. “Good cause” is not defined, but rather left to the FDA's discretion. Possible penalties for violation include banning interstate commerce of the drug or civil monetary penalties.3, 4, 5

The FDA maintains two databases on PMRs/PMCs. The Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) is the FDA's internal, private database. The Postmarketing Study and Clinical Trial Requirements and Commitments Database is a publicly available subset of all PMRs/PMCs in DARRTS.^6,7 It contains only postmarketing studies that were either open or closed within the past year at the time of data retrieval, and information for postmarketing studies closed more than a year before the date the data are extracted is not included.

PMRs/PMCs are categorized in three ways. First, they are assigned a category: pending, ongoing, delayed, terminated, submitted, fulfilled, or released. Second, the PMRs/PMCs are classified as open (pending, ongoing, delayed, submitted, or terminated) or closed (fulfilled or released). Third, open PMRs/PMCs are further classified as on-schedule (pending, ongoing, or submitted) or off-schedule (delayed or terminated). Off-schedule PMRs/PMCs have missed at least one date from their submitted timetable.⁶

In a 2013 study, Fain et al. reviewed the status of all postmarket studies from 2007-2011.⁸ The proportion of studies not started decreased from 2007 (56.7%) to 2011 (43.5%). Those delayed increased from 2007 (6.8%) to 2011 (13.5%). Those terminated or completed also increased, from 2007 (8.8%) to 2011 (16.4%). Despite these improvements, the proportion not started remained high, and the proportion terminated or completed remained low, reinforcing concerns about how postmarket studies are managed.⁸ Woloshin et al. considered PMR/PMC data from 2009 to 2010. They found that after 5–6 years, 20% of postmarketing studies had not been started, 25% were delayed, and 54% were completed. They concluded that although the FDA's processes for postmarketing studies had improved, additional improvements were necessary.⁹ Using data from the Postmarketing Study and Clinical Trial Requirements and Commitments Database file, Wallach et al. found only 166 out of 437 (38%) PMRs for 97 medications and biologics were classified as fulfilled.¹⁰

Both the United States Government Accountability Office (GAO) and the Department of Health and Human Services Office of Inspector General (OIG) have evaluated the FDA's postmarketing processes since the enactment of PDUFA IV. In 2015, the GAO found the FDA lacks reliable, readily accessible data for tracking safety issues and postmarket studies. The FDA's Center for Drug Evaluation and Research's internal evaluations of DARRTS found problems with data completeness, timeliness, and accuracy. These problems prevent the FDA from publishing statutorily required reports on time and restrict its ability to conduct effective oversight of postmarket studies.⁷ In 2016, the OIG conducted a follow up of a 2006 study, encompassing fiscal years (FY) 2008–2014 and focusing on PMRs (since PMCs are voluntary). The majority of PMRs were related to NDAs, many of which had been issued through expedited programs. Applicants completed most PMRs on schedule, but one-third of PMRs were pending in FY 2014. Additionally, the FDA continued to have problems with its data system and workflows.¹¹

This study provides an updated evaluation of the FDA's oversight of PMRs/PMCs from 2011–2014 and compared it to Woloshin et al.'s 2009-2010 data.